Hemorrhagic shock is the commonest and most lethal complication of portal hypertension (PHT). Patients with PHT tolerate massive hemorrhage poorly, with a high risk of developing renal failure, and adult respiratory distress syndrome. Current treatment modalities may actually aggravate the underlying causes of the bleeding. Our ability to develop rational treatment for shock in portal hypertension depends upon a more thorough understanding of the portal vascular response. Recent work has indicated that in PHT, the portal vasculature becomes "hyperdynamic", due in part to excess amounts of prostacyclin (PGI2), a vasodilator produced by the mesenteric vessels; and a diminished response to endogenous vasoconstrictors (angiotensin II, arginine vasopressin). Following hemorrhage and volume resuscitation, portal pressure actually rises to higher than baseline, recreating the risk factors for continued bleeding. Our laboratory has recently shown this abnormal hemodynamic response to hemorrhage/resuscitation in PHT may possibly be mediated by an abnormal response of the splanchnic venous and mesenteric arterial vasculature to angiotensin II, AVP, and PGI2. This proposal seeks to determine the relationship of the putative hormonal mediators of splanchnic blood flow: PGI2, angiotensin II, and arginine vasopressin (AVP) in the abnormal vascular response to hemorrhagic shock in PHT. Using both the partial portal vein ligation model of PHT and the bile duct ligated model of cirrhosis in the rabbit, hemorrhage and resuscitation will be produced in normal and PHT animals with and without specific blockade/agonists. Prostanoid and peptide levels/action will be measured as well as systemic, splanchnic, and portocollateral hemodynamics. In the same model, PGI2, angiotensin II, and AVP vascular receptors will be assayed. Studies to determine the mechanisms underlying the splanchnic vascular response to hemorrhage, and the response to hormonal action will be done. These experiments should provide information central to our understanding of portal hypertension and hemorrhagic shock; and directly contribute to development of clinically effective treatment programs.